Stroke is a leading cause of disability and death worldwide. The complex process of reperfusion after ischemic stroke (IS), characterized by middle cerebral artery occlusion, involves factors such as neuroinflammation and oxidative stress, which may be modified by biological sex. Additionally, individuals affected by IS may develop increased susceptibility to secondary infections, which can culminate in sepsis and exacerbate stroke-related neurological damage. This study aimed to evaluate the effect of post-IS sepsis on long-term cerebral oxidative changes in male and female rats.

Two-month-old male and female Wistar rats were subjected to a model of IS by 60-minute middle cerebral artery occlusion (MCAO) or sham surgery. Seven days after IS, rats underwent sepsis induction by cecal ligation and puncture (CLP). Animals were randomly assigned to SHAM+SHAM, MCAO+SHAM, SHAM+CLP, and MCAO+CLP groups. Eight days later, brain structures (hippocampus, frontal cortex, posterior cortex, and striatum) were collected to assess myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) levels, and catalase (CAT) activity.

In males, increased MPO activity was observed in all analyzed brain regions in the MCAO+CLP group, indicating intensified inflammatory response. Increased N/N levels and reduced CAT activity were also detected, especially in the frontal cortex and hippocampus, suggesting a persistent pro-oxidant environment. In females, combined injury effects were more localized. MPO activity was reduced in the frontal cortex and hippocampus in the MCAO+CLP group, while N/N levels showed a regional pattern, with increases in some structures and decreases in others. CAT activity was reduced only in the hippocampus.

The findings reinforce that biological sex influences cerebral vulnerability to sepsis occurring after ischemic stroke, with males being more susceptible to long-term exacerbation of oxidative changes. These data highlight the importance of considering sexual dimorphism in understanding the pathophysiology of complex neurological injuries and in designing personalized therapeutic approaches.